title: Methionine adenosyltransferase 2B, HuR, and sirtuin 1 protein cross-talk impacts on the effect of resveratrol on apoptosis and growth in liver cancer cells.
abstract: Resveratrol is growth-suppressive and pro-apoptotic in liver cancer cells. Methionine adenosyltransferase 2B (MAT2B) encodes for two dominant variants V1 and V2 that positively regulate growth, and V1 is anti-apoptotic when overexpressed. Interestingly, crystal structure analysis of MAT2B protein (MATβ) protomer revealed two resveratrol binding pockets, which raises the question of the role of MAT2B in resveratrol biological activities. We found that resveratrol induced the expression of MAT2BV1 and V2 in a time- and dose-dependent manner by increasing transcription, mRNA, and protein stabilization. Following resveratrol treatment, HuR expression increased first, followed by SIRT1 and MAT2B. SIRT1 induction contributes to increased MAT2B transcription whereas HuR induction increased MAT2B mRNA stability. MATβ interacts with HuR and SIRT1, and resveratrol treatment enhanced these interactions while reducing the interaction between MATβ and MATα2. Because MATβ lowers the Ki of MATα2 for S-adenosylmethionine (AdoMet), this allowed steady-state AdoMet level to rise. Interaction among MATβ, SIRT1, and HuR increased stability of these proteins. Induction of MAT2B is a compensatory response to resveratrol as knocking down MAT2BV1 potentiated the resveratrol pro-apoptotic and growth-suppressive effects, whereas the opposite occurred with V1 overexpression. The same effect on growth occurred with MAT2BV2. In conclusion, resveratrol induces HuR, SIRT1, and MAT2B expression; the last may represent a compensatory response against apoptosis and growth inhibition. However, MATβ induction also facilitates SIRT1 activation, as the interaction stabilizes SIRT1. This complex interplay among MATβ, HuR, and SIRT1 has not been previously reported and suggests that these proteins may regulate each other's signaling.
authors.affiliation: Division of Gastroenterology and Liver Diseases, University of Southern California Research Center for Liver Diseases, Keck School of Medicine, the University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Heping
authors.initials: H
authors.lastname: Yang
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Zheng
authors.forename: Tony W H
authors.initials: TW
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Peng
authors.forename: David
authors.initials: D
authors.lastname: Fernandez-Ramos
authors.forename: María L
authors.initials: ML
authors.lastname: Martínez-Chantar
authors.forename: Adriana L
authors.initials: AL
authors.lastname: Rojas
authors.forename: José M
authors.initials: JM
authors.lastname: Mato
authors.forename: Shelly C
authors.initials: SC
authors.lastname: Lu
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects*; D051959:ELAV Proteins / Q000096:biosynthesis* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008716:Methionine Adenosyltransferase / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D020871:RNA Stability / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051959:ELAV Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D013267:Stilbenes; C527162:MAT2B protein, human; D008716:Methionine Adenosyltransferase; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D000077185:Resveratrol
keywords: Apoptosis; Cell Growth; HuR; Liver Cancer; Methionine Adenosyltransferase 2B; Resveratrol; Sirt1